Insights into the novel function of system Xc- in regulated cell death.

System Xc-, also named cystine/glutamate antiporter, is an important intracellular antioxidant element. It is composed of the light chain SLC7A11 (xCT) and the heavy chain SLC3A2 (4F2hc) and functions as raw materials for the synthesis of glutathione (GSH). Recent studies have demonstrated that system Xc- plays an important role in different types of regulated cell death, which is referred to cell death controlled by dedicated molecular machinery. It has been shown that system Xc- involves in ferroptosis, apoptosis, and autophagy-dependent cell death, contributing to different diseases and drug resistance, such as cancer, neurological disorders, and cisplatin resistance to cancers. To date, the intervention of system Xc- by its inhibitors or activators displays a beneficial effect on the treatment of certain diseases. In this review, we summarize recent findings on the role of system Xc- in regulated cell death, including molecular mechanisms and potential therapeutic applications.